Mechanisms through which exercise reduces symptom severity and/or functional impairment in posttraumatic stress disorder (PTSD)

Results

We identified 11870 records. The PRISMA flow diagram is presented in Figuare 1. A total of 11 studies with data from 771 participants were eligible for inclusion.The additional texts included secondary analyses, abstracts, trial registries, and protocol papers.

Figure 1: PRISMA flow diagram

Study description

10 of the studies were RCTs, and 1 was a crossover RCT (Greene & Petruzzello, 2022).The specific intervention and comparison groups for the 11 eligible studies (13 comparisons) are presented in Table 1.

Study	Intervention	Comparison	Exercise type	Therapy	TAU	Attention control
Bryant2023	exercise + therapy	attention control + therapy	aerobic	exposure therapy	NA	static stretching
Voorendonk2023	exercise + therapy	attention control + therapy	mixed	PE + EMDR	NA	guided (creative) tasks
Nordbrandt2020	exercise + TAU	TAU	mixed	NA	combination: medical doctor, 1 to 2 sessions with social worker / psychologist	NA
Rosenbaum2014	exercise + TAU	TAU	mixed	NA	combination: individual and group psychotherapy, pharmacotherapy	NA
Young-McCaughan2022b	exercise + therapy	therapy only	aerobic	imaginal exposure	NA	NA
Huseth2022	exercise only	WLC	aerobic	NA	NA	NA
Young-McCaughan2022a	exercise only	TAU	aerobic	NA	self-care intervention delivering educational and instructional information	NA
Whitworth2019a	exercise only	attention control	anaerobic	NA	NA	videos on various educational topics (excluding exercise and mental health).
Whitworth2019b	exercise only	attention control	anaerobic	NA	NA	videos on various educational topics (excluding exercise and mental health).
Crombie2021	exercise + extinction learning	attention control + extinction learning	aerobic	extinction learning	NA	NA
Greene2022a	exercise only	attention control	mixed	NA	NA	remained sedentary in the lab
Greene2022b	exercise only	attention control	aerobic	NA	NA	remained sedentary in the lab
Powers2015	exercise + therapy	therapy alone	aerobic	prolonged exposure	NA	NA

Aerobic = physical performance behaviour pattern that increases heart rate and respiration while using large muscle groups repetitively and rhythmically; anaerobic = physical performance behaviour pattern that is performed in short intense bursts with limited oxygen intake; mixed = combination of aerobic and anaerobic exercise. TAU = treatment as usual; WLC = waiting list control.

Table 1: Specific interventions for all the included studies

8 of the 11 studies were included in the meta-analyses (Bryant et al., 2023; Huseth, 2021; Nordbrandt et al., 2020; Rosenbaum et al., 2015; Voorendonk et al., 2023; Whitworth et al., 2019a; Whitworth et al., 2019b; Young-McCaughan et al., 2022). Meta-analysis was not feasible for 3 of the 11 studies (Crombie et al., 2021a; Greene & Petruzzello, 2022; Powers et al., 2015). Three of the studies provided follow-up PTSD outcome data which were insufficient for synthesis, which were synthesized descriptively without meta-analysis (Crombie et al., 2021a; Greene & Petruzzello, 2022; Powers et al., 2015). Three studies examined putative mediators which was not sufficient to carry out a meta-analysis (Crombie et al., 2021a; Powers et al., 2015; Whitworth et al., 2019a).

Study characteristics of the 8 studies included in the meta-analysis are are presented in Table 2. From these 8 studies, there were 9 eligible comparisons. One study presented findings from two independent comparisons, including a total of four distinct intervention groups (Young-McCaughan et al., 2022). One of the first authors published findings from two different but methodologically similar trials in the same year (Whitworth et al., 2019a; Whitworth et al., 2019b).

Study	Year	N	Intervention	Comparison	PTSD tool	Trial registered	Exercise type	Exercise intensity	Intervention length	FU1	FU2	Country
Bryant2023	2023	130	exercise + therapy	attention control + therapy	CAPS-IV	yes	aerobic	high	10 weeks	34 weeks	NA	Australia
Voorendonk2023	2023	120	exercise + therapy	attention control + therapy	PCL-5	yes	mixed	moderate	12 weeks	26 weeks	NA	Netherland
Nordbrandt2020	2020	224	exercise + TAU	TAU	HTQ	yes	mixed	moderate	20 weeks	NA	NA	Denmark
Rosenbaum2014	2014	81	exercise + TAU	TAU	PCL-4	yes	mixed	high	12 weeks	NA	NA	Australia
Young-McCaughan2022b	2022	36	exercise + therapy	therapy only	PCL-5	no	aerobic	high	8 weeks	12 weeks	32 weeks	USA
Huseth2022	2022	21	exercise only	WLC	PCL-5	no	aerobic	moderate	8 weeks	NA	NA	USA
Young-McCaughan2022a	2022	36	exercise only	TAU	PCL-5	no	aerobic	high	8 weeks	12 weeks	32 weeks	USA
Whitworth2019a	2018	30	exercise only	attention control	PDS-5	no	anerobic	high	3 weeks	NA	NA	USA
Whitworth2019b	2019	22	exercise only	attention control	PDS-5	no	anerobic	high	3 weeks	NA	NA	USA

TAU = treatment as usual; WLC = waiting list control; CAPS-IV = Clinician-Administered PTSD Scale - 4th edition; PCL-4 = PTSD Checklist - version 4; PCL-5 = PTSD Checklist - version 5; PDS-5 = Posttraumatic Diagnostic Scale – version 5; HTQ = Harvard Trauma Questionnaire; Aerobic exercise = physical performance behaviour pattern that increases heart rate and respiration while using large muscle groups repetitively and rhythmically; anaerobic exercise = physical performance behaviour pattern that is performed in short intense bursts with limited oxygen intake; mixed exercise = combination of aerobic and anaerobic exercise; USA = United States of America.

Table 2: Study characteristics of the 8 studies included in the meta-analysis.

Study characteristics of the 3 studies not included in the meta-analysis are are presented (Extended data). From these 3 studies, there were 4 eligible comparisons. One study reported two comparisons (Greene & Petruzzello, 2022).

Study	Year	N	Intervention	Comparison	Trial registered	Exercise type	Exercise intensity	Intervention length	Country
Crombie2021	2021	38	exercise + extinction learning	attention control + extinction learning	yes	aerobic	moderate	3 days	USA
Greene2022a	2022	24	exercise only	attention control	no	anaerobic	high	130 min	USA
Greene2022b	2022	NA	exercise only	attention control	no	aerobic	moderate	130 min	USA
Powers2015	2015	9	exercise + therapy	therapy alone	yes	aerobic	moderate	12 weeks	USA

Aerobic exercise = physical performance behaviour pattern that increases heart rate and respiration while using large muscle groups repetitively and rhythmically; anaerobic exercise = physical performance behaviour pattern that is performed in short intense bursts with limited oxygen intake; USA = United States of America.

Table 3: Study characteristics of the 3 studies not included in the meta-analysis.

Primary outcome

PTSD Symptom Severity

Risk of bias for the PTSD symptom severity

The results of the risk of bias assessment per domain and study for the primary outcome, PTSD symptom severity is presented below in Figure 2 of the Extended Data. Nine studies reported PTSD outcome data post-intervention. Two studies did not report PTSD outcome data (Crombie et al., 2021a; Greene & Petruzzello, 2022). Five of the nine studies had an overall high risk of bias, three had some concerns, and only one was had low risk of bias. High risk of bias was mainly due to deviations from intended intervention (D2)(Voorendonk et al., 2023; Whitworth et al., 2019a; Whitworth et al., 2019b), missing outcome data (D3)(Rosenbaum et al., 2015; Voorendonk et al., 2023; Whitworth et al., 2019a; Whitworth et al., 2019b), and selection of reported results (D5)(Voorendonk et al., 2023; Young-McCaughan et al., 2022).

Figure 2 Results of the risk of bias assessment per domain and overall for the PTSD severity outcome

Post-intervention (weeks)

For the studies included in the meta-analyses, the earliest study was performed in 2014, while the most recent study was performed in 2023. The median sample size across the studies was 36 participants per study. The median of the mean participant age was 37 years (ranging from 29 to 50 years). Intervention length ranged from 3 weeks to 20 weeks, with a median of 8 weeks.

8 studies provided data for PTSD symptom severity and contributed 9 effect measures to the PTSD symptom severity meta-analysis. The forest plot for PTSD symptom severity is presented in Figure 3.

Figure 3: Meta-analysis of the effects of exercise on PTSD symptom severity.

The meta-analysis found no evidence of a difference in PTSD symptom severity reduction between exercise and comparison groups (SMD = -0.08, 95% CI -0.24 to 0.07). No statistical heterogeneity was observed (τ2=0).

Subgroup Analyses and Meta-regressions

Subgroup analysis by exercise intensity

The test for interaction found some evidence of a difference between studies with moderate intensity and those with high-intensity exercise (Figure 4). We found some evidence that the effect of exercise might be larger in studies of high-intensity exercise compared to studies with moderate intensity

Figure 4: Sub-group analysis of the effects of exercise on PTSD symptom severity by exercise intensity

Subgroup analysis by specific exercise type

We did not find any important differences between the effects of aerobic, anaerobic, or mixed exercise groups (Figure 5).

Figure 5: Sub-group analysis of the effects of exercise on PTSD symptom severity by specific exercise type

Subgroup analysis by exercise alone or tau/therapy augmented by exercise.

TWe found that studies with exercise alone as intervention were associated with larger effects than those in studies where patients were additionally given treatment-as-usual or psychotherapy (Figure 6).

Figure 6: Sub-group analysis of the effects of exercise on PTSD symptom severity by exercise alone or TAU/therapy augmented by exercise

Meta-regression by intervention length

We performed a meta-regression for the intervention duration, despite the fact that we had only 9 studies (Figure 7). The meta-regression analysis yielded a coefficient of 0.02 (95% CI: -0.01, 0.05), indicating that for every additional week, the standardized mean difference (SMD) in PTSD symptoms increased by 0.02. This suggests there was no meaningful association between intervention duration and PTSD symptom severity

Figure 7: Meta-regression of the effects of exercise on PTSD symptom severity by intervention length

Heterogeneity explained by covariates

Moderator	Category	\(\beta\)	95% CI	𝞽2
Overall effect	-	-0.08	-0.24 to 0.07	0
Exercise intensity	-	-	-	-
	Moderate	0.04	-0.17 to 0.25	0
	High	-0.23	-0.45 to 0	0
Exercise type	-	-	-	-
	Aerobic	-0.16	-0.43 to 0.1	0
	Anaerobic	-0.52	-1.13 to 0.1	0
	Mixed	0.01	-0.19 to 0.21	0
Exercise augmentation	-	-	-	-
	Exercise alone	-0.38	-0.77 to 0.02	0
	TAU/therapy + augmented	-0.03	-0.2 to 0.14	0
Intervention length	per unit (Week) increase	0.02	-0.01 to 0.05	0

Sensitivity Analyses

We examined the robustness of the findings for the primary outcome by excluding studies with high risk of bias (Figure 8). 3 studies included in the meta-analyses were rated as low or some concerns. WWhen restricting the analysis to the three studies with low risk of bias or some concerns, the effect of exercise on PTSD symptoms severity decreased only slightly SMD = -0.06 (95% CI: -0.27 , 0.14). For reference, the main effect size for the primary outcome was SMD = -0.08 (95% CI: -0.24 , 0.07), so the results do not change substantially.

Figure 8: Meta-analysis of the effects of exercise on PTSD symptom severity when excluding studies with high risk of bias

Reporting bias

Visual inspection of the funnel plot of standard error Hedges’ g suggested possible publication bias in favour the of exercise group.

There was insufficient studies to test for small study effect. The forest plot below shows the meta-analysis results of the primary outcome, PTSD symptom severity, ordered by the precision of the studies is presented in Figure 9. The smaller studies showed larger effects favoring the exercise groups compared to the larger studies which cluster around the line of no effect.

Figure 9: Forest plot of the meta-analysis results of the primary outcome ordered by the precision of the studies

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Secondary outcomes

Treatment Dropout

Post-intervention (weeks)

8 studies provided data for treatment dropout, and contributed 9 effect measures to the treatment dropout meta-analysis. The forest plot for the risk of treatment dropout presented in Figure 10.

Figure 10: Meta-analysis of the dropout rates between the intervention and control groups

No evidence of a difference in treatment dropout between exercise and comparison groups (RR = 1.28, 95% CI 0.67 to 2.45) was found and there was large heterogeneity, as shown by the prediction interval (0.16 to 10.15).

Functional impairment

Two studies examined the effects of exercise on functional impairment post-intervention (Nordbrandt et al., 2020; Voorendonk et al., 2023). Nordbrandt et al., 2020 compared treatment as usual (TAU) which constituted of psychotherapy in the form of CBT and acceptance and commitment therapy (n = 104) – with TAU with basic body awareness therapy (n = 105), and exercise plus TAU (n = 109). They did not find any evidence that exercise +TAU is more effective than either TAU or TAU +basic body awareness therapy. Voorendonk et al. compared an 8-day intensive trauma-focused therapy (TFT) programme with (n = 59) and without exercise (n = 60). The intensive TFT programme consisted of daily prolonged exposure, EMDR therapy and psychoeducation complemented with physical activities for the exercise group and controlled mixtures of creative tasks for the control group. They did not find any evidence that exercise is more effective than the control in improving quality of life (Voorendonk et al., 2023).

PTSD symptom clusters

Two of the 11 studies examined the effects of exercise on PTSD symptom clusters, namely avoidance, re-experiencing, hyperarousal, as well as negative cognitions and mood (Whitworth et al., 2019a; Whitworth et al., 2019b). One study reported significantly lower levels of avoidance symptoms (Cohens’ d = 1.26; 95% CI [0.39, 2.14]) and hyperarousal symptoms (d = 0.90; 95% CI [0.06, 1.74]) in the exercise group (n = 15) relative to the control group (n = 15) post-intervention (Whitworth et al., 2019a).While intrusion (d = 0.67; 95% CI [−0.15, 1.49]) and mood and cognitive symptoms (d = 0.34; 95% CI [−0.47, 1.14],) did not differ between the exercise group (n = 15) and the control group (n = 15) post-intervention (Whitworth et al., 2019a). The other study found no significant between-group differences (p>0.05) between the exercise (n = 9) and comparison (n = 10) groups for intrusion (d= -0.65 vs d = -1.25), avoidance (d = -0.95 vs d = -0.92) mood and cognitive symptoms (d= -0.73 vs d = -0.70) , and hyperarousal symptoms (d= -0.43 vs d = -0.59)(Whitworth et al., 2019b).

Loss of PTSD diagnosis

Only one study reported data on loss of PTSD diagnosis post-intervention (Voorendonk et al., 2023). Loss of diagnosis was high in both the exercise and comparison groups. Findings based on the CAPS-5 showed that the loss of PTSD diagnosis post-intervention did not differ between the exercise and the control groups (80.0% versus 82.7%); X2[1] = 0.13, p = 0.72).

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Mediators of the effect of exercise on PTSD-related symptoms

Three studies examined putative mediators of exercise, but the available data was insufficient to carry out a synthesis (Crombie et al., 2021a; Powers et al., 2015; Whitworth et al., 2019a). In Crombie et al. 35 participants completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol. Each participant was randomized to complete either intervention (moderate-intensity aerobic exercise) or a light-intensity control condition following extinction training on day 2. Blood samples were obtained before and after intervention or control condition. protocol involving fear acquisition, extinction, and recall. They examined whether the effect of exercise on threat expectancy ratings during the extinction recall phase was mediated by brain-derived neurotrophic factor (BDNF), anandamide (AEA), 2-arachidonoylglycerol (2-AG), and homovanillic acid (HVA) (Crombie et al., 2021a). Threat expectancy ratings evaluate an individual’s anticipation levels toward encountering threatening situations. Individuals with PTSD often exhibit elevated ratings. Decreasing these anticipations may lead to a reduction in the severity of PTSD symptoms. For the total effect, the exercise group exhibited lower threat expectancy ratings following reinstatement than the comparison group (between group d = 0.75; t(33) = -2.233, p = .032). Circulating concentrations of BDNF (95% CI for the indirect effect = -0.941 to -0.005) and AEA (95% CI for the indirect effect= -0.623 to -0.005) following exercise mediated the relationship between exercise and reduced threat expectancy ratings following reinstatement. While 2-AG (95% CI for the indirect effect= -0.050 to 0.210) and HVA (95% CI for the indirect effect = -0.190 to 0.134) did not reach statistical significance.

Powers examined BDNF levels as a potential mediator of the relationship between exercise and PTSD symptom severity (Powers et al., 2015). Post-intervention, the exercise increased BDNF concentration to a greater degree than control condition, yielding a significantly large (>0.8) between group effect size (d = 1.08). Likewise, exercise group had a significantly greater reduction in PTSD symptom than the control conduction, yielding a very large between group effect size (d = 2.65). These findings suggest that BDNF levels might mediate the relationship between exercise and PTSD symptom reduction.

Whitworth et al. examined whether exercise is associated with changes in cognitive appraisal, perceived exertion, affect, arousal, and distress in a sample of 22 adults and whether these changes impact on PTSD symptoms (Whitworth et al., 2019a). They found changes in the perception of the resistance training sessions (cognitive appraisal; b = 7.1, p = 0.02) and perceived exertion (b= -3.1, p = 0.01) mediated the relationship between exercise and PTSD symptom severity. Affect (b = 0.82, p = 0.63), arousal (b = 2.4, p = 0.12), and distress (b = 0.18, p = 0.17) did appear to have a mediating effect. These outcomes were observed at the conclusion of the 3-week intervention.

Risk of bias for the mediation studies

The results of the risk of bias assessment for the mediation analyses are presented in Figure 11. Even though two of the three mediation studies had only some concerns within the non-mediation-specific (D1-D5) components of the revised ROB2 tool (Crombie et al.,2021a; Powers et al., 2015), all of the three studies had an overall high risk of bias mainly due to the deviations in mediation-specific domains (D6-D9) (Crombie et al.,2021a; Powers et al., 2015; Whitworth et al., 2019). In the domains (D7 and D8), 100% of the mediation studies had a high risk of bias underscoring the current methodological limitation in mediation analysis and handling confounding in mediation studies (Crombie et al.,2021a; Powers et al., 2015; Whitworth et al., 2019).

Figure 11 Results of the risk of bias assessment per domain and overall for the mediation outcomes

SUMMARY OF THE EVIDENCE

The primary outcome was efficacy in reducing overall PTSD symptom severity in patients with PTSD. The summary of the evidence on PTSD symptom severity outcome for PTSD is reported below.

Outcome	Summary of the association	Within-study biases	Across-studies biases	Indirectness	Other Bias
PTSD symptom severity	Studies = 8 (9 comparisons), Participants = 700; Random effects: SMD = -0.08, 95%CI: -0.24, 0.07 Low to no statistical heterogeneity. We found some evidence that the effect of exercise might be larger in studies of high-intensity exercise compared to studies with moderate intensity; and that studies with exercise alone as intervention were associated with larger effects than those in studies where patients were additionally given treatment-as-usual or psychotherapy. We did not find evidence of differences between the effects of aerobic, anaerobic, or mixed exercise groups; or that intervention duration (in weeks) was related to post-intervention PTSD symptom severity.	High risk Overall, 5 studies had high risk of bias, for 3 studies we had some concerns, and 1 had a low risk of bias. Bias was mainly due to deviations from the intended intervention, missing outcome data, and selection of reported results. We expect that the bias exaggerates the effect of the intervention.	High risk It appears that the smaller studies showed larger effects favouring the intervention. Possibly the effect of exercise is exaggerated. Small number of studies per subgroup Data from only 9 studies. Additionally, studies may change these findings	Some concerns Participants Some concerns (no data for child and adolescence. Only adults Intervention: Some concern (evidence of a larger effect for high-intensity compared to moderate-intensity exercise) Control: Some concern (some evidence of a difference between exercise alone compared with those with exercise in addition to psychotherapy or TAU) Outcome: Low risk (Validated PTSD symptom severity measurement scales)	Some concerns Three studies not included in the meta-analysis due to insufficient data .